Clinical and Pathologic Landscapes of Delta-Like Ligand 3 and Seizure-Related Homolog Protein 6 Expression in Neuroendocrine Carcinomas.

Purpose: Delta-like ligand 3 (DLL3) and seizure-related homolog protein 6 (SEZ6) are appealing drug targets in neuroendocrine carcinomas (NECs) given their preferential expression on the tumor cell surface compared with normal cells. We aimed to describe the landscape of these proteins across NECs from eight different primary sites.

Patients and methods: We used immunohistochemistry to assess 124 NEC tumor samples from any primary site for DLL3 and 53 for SEZ6 and defined positivity as ≥1% staining.

Results: DLL3 and SEZ6 were commonly expressed in our cohort (97 of 124, 78% and 43 of 53, 81% positivity rates, respectively) and frequently coexpressed when both tested (35 of 53, 66%). NECs of the breast, prostate, and GI system had the highest rates of DLL3 positivity (2 of 2, 100%; 15 of 16, 94%; and 14 of 17, 82%, respectively); all primary sites except lung exhibited 100% positivity rates for SEZ6. DLL3 expression and SEZ6 expression were seen in transformed NECs (12 of 17, 71% and 3 of 4, 75%, respectively) and in brain metastases (5 of 7, 71% and 1 of 2, 50%, respectively). Expression of both proteins tended to remain stable among 10 patients with serial biopsies. DLL3 expression did not affect progression-free survival (PFS) on first-line platinum/etoposide with or without immunotherapy among patients with metastatic lung NEC (median PFS 5.3 v 5.7 months in DLL3⁺ v DLL3^-, P = .9) but was associated with longer overall survival (median 12.5 v 2.6 months, P = .03).

Conclusion: We describe the landscape of DLL3 and SEZ6 coexpression across NECs, establishing a broad-based cohort of patients who might derive benefit from therapeutics in development targeting these cell surface determinants.